The Journal of allergy and clinical immunology · 2025
Lipopolysaccharide-responsive and beige-like anchor protein (LRBA) functional deficiency caused by biallelic LRBA missense variants characterized by Evans syndrome or colitis.
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Chiang Samuel C C, Yang Li, Owsley Erika, Husami Ammar, Akeno Nagako, Cobb Cristina, Hartog Nicholas L, Elizalde Araceli, Seroogy Christine M, Blanchard-Rohner Geraldine, Peng Xiao P, Brager Rae, Buchbinder David, Cook Eleanor, Phillips Lindsay, Plecas Maricic Snezana, Kalashnikova Tatiana, Derfalvi Beata, Dimitriades Victoria R, Murguía-Favela Luis E, Gutierrez Maria J, Shrikhande Anitha, Steele MacGregor, Wilson Jo L, Wright Nicola A M, Marsh Rebecca, Bleesing Jack, Jordan Michael B, Marwaha Ashish K
Аннотация
BACKGROUND: Biallelic loss-of-function mutations in the lipopolysaccharide-responsive and beige-like anchor (LRBA) gene lead to a severe syndrome of early-onset immune dysregulation called LRBA deficiency. Monoallelic CTLA4 mutations lead to a similar phenotype. In both conditions, cytotoxic T lymphocyte-associated protein 4 (CTLA-4) levels are significantly decreased. In previously reported cases of symptomatic disease associated with LRBA pathogenic variants, patients usually have severely decreased or absent LRBA protein levels.
OBJECTIVE: We describe 5 patients with biallelic missense variants in the LRBA gene presenting predominantly with Evans syndrome or colitis.
METHODS: LRBA and CTLA-4 levels were investigated in LRBA missense, "classic" LRBA and in CTLA-4 insufficiency samples.
RESULTS: Surprisingly, all 5 LRBA missense patients had normal expression of LRBA protein. However, CTLA-4 intracellular expression was reduced to similar levels as those seen in patients with CTLA-4 insufficiency at resting state. Lower levels of surface CTLA-4 are seen on cell activation, indicating that these LRBA variants lead to reduced CTLA-4 cell surface expression. Several of the missense variants are shared between unrelated patients in the cohort, suggesting a mutational hot spot or founder effect for those with shared ancestry.
CONCLUSION: Novel LRBA deficiency variants result in quantitative or qualitative LRBA defects, leading to reduced intracellular resting levels and induced surface levels of CTLA-4.
OBJECTIVE: We describe 5 patients with biallelic missense variants in the LRBA gene presenting predominantly with Evans syndrome or colitis.
METHODS: LRBA and CTLA-4 levels were investigated in LRBA missense, "classic" LRBA and in CTLA-4 insufficiency samples.
RESULTS: Surprisingly, all 5 LRBA missense patients had normal expression of LRBA protein. However, CTLA-4 intracellular expression was reduced to similar levels as those seen in patients with CTLA-4 insufficiency at resting state. Lower levels of surface CTLA-4 are seen on cell activation, indicating that these LRBA variants lead to reduced CTLA-4 cell surface expression. Several of the missense variants are shared between unrelated patients in the cohort, suggesting a mutational hot spot or founder effect for those with shared ancestry.
CONCLUSION: Novel LRBA deficiency variants result in quantitative or qualitative LRBA defects, leading to reduced intracellular resting levels and induced surface levels of CTLA-4.